The present invention relates to the use of indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano [3,4-b]indole, 1,3,4,9-tetrahydrothiopyrano [3,4-b]indole, 1,2,3,4-tetrahydro-4H carbazole or 2,3,4,9-tetrahydro-1H-carbazole nucleus, such as etodolac, in the treatment of chronic lymphocytic leukemia, and B-cell and T-cell lymphomas.
Chronic lymphocytic leukemia (CLL) is a heterogeneous group of diseases characterized by different maturation states of the B-cells and T-cells, which are related to the aggressiveness of the disorder. Accordingly, CLL is commonly classified into separate categories, including B-cell chronic lymphocytic leukemia of classical and mixed-types, B-cell and T-cell prolymphocytic leukemia, hairy-cell leukemia and hairy-cell variant, splenic lymphoma with circulating villous lymphocytes, large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma syndrome and leukemic phases of malignant lymphomas of both B-cell and T-cell types.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by proliferation and accumulation of B-lymphocytes that appear morphologically mature but are biologically immature. B-CLL typically occurs in persons over 50 years of age. This disorder accounts for 30% of leukemias in Western countries, with 10,000 new cases being diagnosed annually in the United States alone. The disorder is characterized by proliferation of biologically immature lymphocytes (lymphocytosis), which typically express low levels of surface immunoglobulins, which upon organ infiltration cause lymph-node enlargement and hepato-splenomegaly. In the advanced stages of the disease, bone marrow occupation by the abnormal lymphocytes causes bone marrow failure, resulting in anemia and thrombocytopenia.
The B-cells in CLL have receptors for mouse erythrocytes, a marker of immature B-cells. An increased number of T-cells has been reported in this disorder with an increase in the number of T-suppressor cells. Typically, an inversion of the T-helper/suppressor ratio results, with increased suppressor T-cells and decreased helper T-cells. The absolute number of natural killer cells may also be increased. In addition, chromosome analysis provides prognostic information about overall survival, in addition to that supplied by clinical data in patients with B-cell CLL.
It has been suggested that certain non-steroidal anti-inflammatory drugs (NSAIDs) may exhibit chemopreventative and anti-neoplastic properties. For example, Piazza et al., Cancer Research 57:2452-2459 (1997), discloses that sulindac (an NSAID that acts as a cyclooxygenase inhibitor) causes regression of and prevents recurrence of colonic adenomas in patients with familial adenomatous polyposis in a manner that appears to be independent of the drug""s cyclooxygenase inhibition activity. Although induction of apoptosis was suggested, the actual mechanism of action of this NSAID in the inhibition of cell growth is poorly understood.
The compound etodolac, 1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]-indole-1-acetic acid, falls generally in the class of NSAIDs and is a cyclooxygenase inhibitor. Etodolac is used to treat mild-to-moderate pain, osteoarthritis, and rheumatoid arthritis. Other related indole compounds have also been shown to exhibit similar activity. For example, U.S. Pat. Nos. 3,843,681, 3,939,178, 3,974,179 and 4,686,213 disclose indole derivatives based on the 1,3,4,9-tetra-hydropyrano[3,4-b]-indole-1-acetic acid nucleus that are stated to exhibit anti-inflammatory, analgesic, antibacterial and/or antifingal activity. Similar 1,2,3,4-tetrahydro-4H-carbazole and 2,3,4,9-1H-carbazole compounds and their use as cyclooxygenase-2 (COX-2) inhibitors for antiarthritic, colorectacl cancer and Alzheimer""s therapy are also disclosed in U.S. Pat. Nos., 5,776,967, 5,824,699 and 5,830,911.
It has now been surprisingly discovered that the number of circulating leukemic lymphocytes in patients suffering from chronic lymphocytic leukemia (CLL), such as B-cell CLL, is reduced by the administration of certain indole compounds, such as the nonsteroidal anti-inflammatory drug etodolac or related indole compounds, in vivo, in vitro, and in situ.
Thus, in one aspect the present invention relates to the discovery that etodolac or related indole compounds reduce the level of leukemic lymphocytes in patients with CLL.
The present invention also relates to the use of etodolac, related indole compounds and/or salts or functional derivatives thereof, in the manufacture of a pharmaceutical composition for the treatment of CLL or B-cell lymphomas.
In yet another aspect, the invention relates to pharmaceutical compositions for the treatment of CLL or B-cell lymphomas, comprising etodolac, related indole compounds and/or salts thereof, as active ingredients, optionally together with pharmaceutically acceptable carriers and/or excipients and/or adjuvants.
It is contemplated that effective indole compounds of this invention are characterized by having a pyrano [3,4-b]indole, thiopyrano [3,4-b]indole or carbazole nucleus bearing a substituent at position 1, said substituent incorporating an acid, ester or amide function therein. These derivatives may be represented by Formula I: 
in which R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxyloweralkyl, lower cycloalkyl, phenyl, benzyl and 2-thienyl; R2 and R3 are the same or different and are each selected from the group consisting of hydrogen and lower alkyl; R4 and R5 are the same or different and are each selected from the group consisting of hydrogen, lower alkyl, xe2x80x94NH2, xe2x80x94NHCHO, xe2x80x94NHCONH2, xe2x95x90NW, oxo, xe2x80x94OH and xe2x80x94OCH3, wherein W is hydroxy, alkoxy, aryloxy, carboxyalkyloxy, arylamino or alkylsulfonylamino; R6 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoroloweralkoxy, benzyloxy, araloxy, lower alkanoyloxy, acyl, amino, nitro, cyano, alkylimido, halo, mercapto, loweralkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido and sulfamoyl; R7 is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl; X is selected from the group consisting of carbon, oxy and thio; Y is selected from the group consisting of carbonyl, 
in which each of R8, R9, R10, R11, R12 and R13 is hydrogen or lower alkyl; and Z is selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, di(lower)alkylamino and phenylamino.
Also included within the scope of this invention are pyrano [3,4-b]indole and thiopyrano [3,4-b]indole derivatives of Formula I in which R6 represents from one to four substituents, which may be present simultaneously, at positions 5, 6, 7 and 8 thereof. The exact nature of such substituents does not have to be limited necessarily by the above definitions of R6, and R6 may also include additional substituents, for example, mercapto, lower alkylthio, trifluoromethyl and other halo(lower)alkyls, amino and sulfamoyl, provided that any two such substituents do not interfere with each others presence. Accordingly the indole derivatives of this invention are represented also by general Formula Ia: 
in which R1, R2, R3, R4, R5, R7, X, Y and Z are as defined above and R6a, R6b, R6c and R6d are the same or different and each is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoroloweralkoxy, benzyloxy, araloxy, lower alkanoyloxy, acyl, amino, nitro, cyano, alkylimido, halo, mercapto, loweralkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido and sulfamoyl.
In yet other aspects of the invention, methods are provided for the treatment of CLL and other lymphomas by administering to a patient in need thereof, a lymphocyte reducing amount of a compound of Formula I or Ia, either alone or together with a pharmaceutically acceptable carrier.